1. Global Health Richard J. Derman, M.D. MPH Chair, Department of Obstetrics and Gynecology, Christiana Care Director, Institute for Women and Children’s Health Research Professor, Obstetrics and Gynecology Thomas Jefferson University

2. Why International Research?  99% of maternal deaths occur in developing countries  23% of pregnant women have no access to antenatal care  39% of women deliver without a skilled birth attendant  The death of a women is associated with major negative outcomes for living children  The same conditions that kill women in the developing world are leading causes of mortality and morbidity in the U.S. Maternal Health Task Force, 2009

3. Why Do Women Die? 530,000 maternal deaths annually  Postpartum hemorrhage  Eclampsia  Infection/Septic Abortion

4. PPH’s Contribution to Mortality and Morbidity  The single most important cause of maternal death worldwide.  At least 1/4 of all worldwide maternal deaths (> 530,000) are due to PPH. (> 530,000) are due to PPH.  14,000,000 cases of pregnancy-related hemorrhage each year with at least 128,000 of these women bleeding to death.  The percentage of all pregnancy-related deaths due to hemorrhage is 19% in the United States.

5. Global Scenario WHO - UNICEF - UNFPA MaternalDeaths(Number) Maternal Mortality Ratio (deaths per 100,000 live births) Life time risk of maternal death 1 in: India 136,00 0 54048 Develope d regions 2,500202,800 World Total 529,00040074

6. PPH Non-Predictable  Two-thirds of women who hemorrhage have no identifiable risk factors  Similar ratio among PP hemorrhage deaths in US  Women who survive often must receive blood transfusion - ↑ risk of hepatitis or HIV WHO Mother-Baby Package, 1998

7. Average Interval from Onset to Death  Ruptured uterus24 hrs  Antepartum hemorrhage12 hrs  Postpartum hemorrhage 2 hrs Maine D. Safe Motherhood Programs: Options and Issues, Center for Population & Family Health, Columbia University,1993.

8. Strategies for Reducing Postpartum Hemorrhage Secondary to Atonic Uterus

9. Active Management of the Third Stage of Labor  Designed to speed the delivery of the placenta by increasing uterine contractions and thus averting uterine atony (60% reduction in risk)  Components –Administration of uterotonic agent (post cord-clamping) –Placenta delivered by controlled cord traction with counter-traction on the fundus –Uterine massage > delivery of placenta FIGO Joint Statement June, 2004

10. Active Management of the Third Stage of Labor without Controlled Cord Traction: A Randomized Non-inferiority Controlled Trial  Uterotonic use likely has greatest impact  Concern over controlled cord traction in rural areas among nonphysicians  If not significant change in bleeding, can recommend against the practice and expand AMTSL to lower level providers Gulmezoglu, M, et al., Reproductive Health, 2009 Jan, 6:2. (World Health Organization)

11. A Randomized Placebo-Controlled Trial of Oral Misoprostol for Prevention of Postpartum Hemorrhage at Four Primary Health Centers of the Belgaum District, Karnataka India  Richard J. Derman, MD, MPH  Bhala Kodkany, MD  V.J. Naik, MD  Ashlesha Patel, MD, MPH  Shiva Goudar, MD  Stacie Geller, PhD  Stanley Edlavitch, PhD

12. Study Sponsors

14. Intervention  Misoprostol or Placebo #3, 200 mcg tablets, orally  Administered within 5 minutes of clamping and cutting of the cord and cessation of cord pulsation

15. Primary Outcome  Objective Measurement of Blood Loss  BRASSS-V ® Blood Collection Drape with Calibrated Receptacle

16. BRASSS-V Blood Collection Drape with Calibrated Receptacle

17. Primary Hypothesis Misoprostol administered during the third stage of labor will significantly reduce the incidence of acute postpartum hemorrhage by 50%.

19. Oral misoprostol in preventing postpartum hemorrhage in resource-poor communities: a randomized controlled trial Lancet 2006; 368: 1248-53 Lancet 2006; 368: 1248-53

20. PPH Rates PPH Rates Primary Outcome Misoprostol (n= 812*) n (%) Placebo(n=805) P- valu e PostpartumHemorrhage (blood loss  500 ml) 53 (6.5) 53 (6.5) 97 (12.0) 97 (12.0) 0.000 1 Severe Postpartum Hemorrhage (blood loss  1,000 ml) 2 (0.2) 2 (0.2) 10 (1.2) ss 10 (1.2) ss

21. One case of postpartum hemorrhage was prevented for every 18 women who received Misoprostol  Price now reduced to 12 cents/dose  Registered in 14 countries in Africa and Asia

22. Postpartum Hemorrhage Rates for Data Review Periods of Randomized Women by Treatment 6.7 9.5 8.3 1.9 6.4 17.7 12.3 9.2 6.5 12.0 0 2 4 6 8 10 12 14 16 18 20 1234Overall Data Review Periods % PPH MisoprostolPlacebo n=256 n=220 n=254 n=219 n=121 n=119 n=215 n=216 n=811 n=808 Goudar SS, et al., Variation in the postpartum hemorrhage rate in a clinical trial of oral misoprostol. J Matern Fetal Neonatal Med. 2008 Aug; 21(8):559-64

23. What Measured Blood Loss Tells Us About Postpartum Bleeding: A systematic review  Prevalence of PPH (>500 ml) 10.55% in 19 studies where blood loss was measured vs. 7.23% with visual estimation  Ongoing debate about changing the definition of PPH – (clinical instability, drop in Hgb of >10% or >750ml) Sloan N, et. al. BJOG, 4/2010

24. Management of PPH Low Resource Settings Is it more cost effective to prevent or to treat?  Aggressive Treatment of PPH –Misoprostol 800-1000 mcg rectally/sublinguinal –UNIJECT ® - Oxytocin  Prefilled, nonrefillable, sterile  Single dose  Auto-disable syringe PATH – Program for Appropriate Technology in Health

25. Inflated condom in a kidney tray

26. Non-inflatable Anti-shock Garment

27. Reducing Morbidity and Mortality of PPH (Lessons learned from the U.S.)  Team training  Use of simulation laboratories  Rapid response team drills –massive transfusion protocol  Hospitals in lowest quartile of deliveries have mortality/hysterectomy rates  71% Bateman B. et al. Anaes-Analg, 2010.

28. Newborn Care Training and Perinatal Mortality in Developing Countries  3.7 million neonatal deaths  3.3 million stillbirths (majority fresh stillbirths)  98% occur in developing countries  An evaluation of community-based interventions is needed Carlo W, et al. NEJM Feb 18, 2010

29. First Breath Trial First Breath Trial  Six country study instituted (DRC, Zambia, India, Pakistan, Guatemala, Argentina)  Train the trainer model  Employed WHO ENC training model –Routine neonatal care –Resuscitation –Thermoregulation –Breast feeding –Skin-to-skin care Carlo W, et al. NEJM Feb 18, 2010

30. Selected GN Research Advances  “FIRST BREATH”: 30% reduction in the rate of stillbirths following basic training in resuscitation and newborn care for birth attendants.  120,000 births and 3,600 birth attendants trained NEJM, 2010; 362:614-623

31. Estimated stillbirth numbers by World Region, 2000 68% Source: Stanton, Lawn et al Lancet 2006 99% Low and middle income countries Total of 3.2 million (2.5 to 4.1 million)

32. Reducing Perinatal Mortality in Community Settings  Site-specific findings in Belgaum are consistent with a 30%  in neonatal mortality in Nepal and a similar reduced risk by training TBAs’ in Pakistan.  Reduction in mortality beyond a certain level likely requires access to facility care with emergency preparedness. Goudar, et al., In Press

33. EMONC The GN is currently conducting a trial employing a package of interventions including:  Home-based lifesaving skills  Training of all birth attendants  Facilitation of transport  Community mobilization  Death audit

34. Global Network Registry Collection of registry data on maternal and neonatal deaths, allowing for and neonatal deaths, allowing for population-based research, identification of effective interventions and development of evidence-based health care policies. N=160,000

35. Next Multi-site Study in Concert with WHO Trial of antenatal steroids to reduce mortality among preterm/low birth weight infants in limited-resource settings.

36. Exposure of Pregnant Women to Indoor Air Pollution (10 sites, 9 countries) Exposure of Pregnant Women to Indoor Air Pollution (10 sites, 9 countries)  Largest survey among pregnant women in developing world  Concerns over cooking with animal dung, crop residue and charcoal  Safety issue relating to open fires indoors  Impact of second hand smoking Data suggests poorer pregnancy outcomes Kadir, MM et al. Acta OB et GYN 2009

37. Global Alliance on Clean Cook Stoves “NICHD joins the Dept of State, the EPA, the CDC, and other federal partners in supporting this initiatives of the UN Foundation to address the health, environmental, economic, and gender risks associated with the use of solid fuels in traditional cook stoves by about half of world’s population” Guttmacher, A

38. Conclusion  We know how to reduce maternal and neonatal mortality  Keys to success must incorporate: Education of all birth providers Education of all birth providers Team training Team training Community involvement Community involvement Implementation and dissemination research Implementation and dissemination research